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Synthesis and biological evaluation of novel N ‐aryl‐ ω ‐(benzoazol‐2‐yl)‐sulfanylalkanamides as dual inhibitors of α‐glucosidase and protein tyrosine phosphatase 1B
Author(s) -
Wang MeiYan,
Cheng XianChao,
Chen XiuBo,
Li Yu,
Zang LanLan,
Duan YuQing,
Chen MingZhu,
Yu Peng,
Sun Hua,
Wang RunLing
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13331
Subject(s) - chemistry , acarbose , ursolic acid , dephosphorylation , protein tyrosine phosphatase , uncompetitive inhibitor , biochemistry , stereochemistry , phosphatase , enzyme , non competitive inhibition , chromatography
α‐Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B ( PTP 1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α‐glucosidase and PTP 1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N ‐aryl‐ ω ‐(benzoazol‐2‐yl)‐sulfanylalkanamides were synthesized and assayed for their α‐glucosidase and PTP 1B inhibitory activities, respectively. Compound 3l , exhibiting the most effective α‐glucosidase inhibitory activity ( IC 50 = 10.96 μ m ( 3l ), IC 50 = 51.32 μ m (Acarbose), IC 50 = 18.22 μ m (Ursolic acid)) and potent PTP 1B inhibitory activity ( IC 50 = 13.46 μ m ( 3l ), IC 50 = 14.50 μ m (Ursolic acid)), was identified as a novel dual inhibitor of α‐glucosidase and PTP 1B. Furthermore, 3l is a highly selective PTP 1B inhibitor because no inhibition was showed by 3l at 100 μ m against PTP ‐ MEG 2, TCPTP , SHP 2, or SHP 1. Subsequent kinetic analysis revealed 3l inhibited α‐glucosidase in a reversible and mixed manner. Molecular docking study indicated that hydrogen bonds, van der Waals, charge interactions and Pi‐cation interactions all contributed to affinity between 3l and α‐glucosidase/ PTP 1B.